Colon Myoelectric Activity Measured After Open Abdominal Surgery with a Noninvasive Wireless Patch System Predicts Time to First Flatus

Journal of Gastrointestinal Surgery (2019) 23:982–989 https://doi.org/10.1007/s11605-018-4030-4

ORIGINAL ARTICLE

Anand Navalgund1 & Steve Axelrod1 & Lindsay Axelrod1 & Shyamali Singhal2 & Khoi Tran3 & Prithvi Legha 3 & George Triadafilopoulos4

Received: 6 July 2018 /Accepted: 22 October 2018 /Published online: 2 November 2018 # 2018 The Society for Surgery of the Alimentary Tract

Abstract Background Passage of flatus after abdominal surgery signals resolution of physiological postoperative ileus (POI) and often, particularly after complex open surgeries, serves as the trigger to initiate oral feeding. To date, there is no objective tool that can predict time to flatus allowing for timely feeding and optimizing recovery. In an open, prospective study, we examine the use of a noninvasive wireless patch system that measures electrical activity from gastrointestinal smooth muscles in predicting time to first flatus. Methods Eighteen patients who underwent open abdominal surgery at El Camino Hospital, Mountain View, CA, were consented and studied. Immediately following surgery, wireless patches were placed on the patients’ anterior abdomen. Colonic frequency peaks in the spectra were identified in select time intervals and the area under the curve of each peak times its duration was summed to calculate cumulative myoelectrical activity. Results Patients with early flatus had stronger early colonic activity than patients with late flatus. At 36 h post-surgery, a linear fit of time to flatus vs cumulative colonic myoelectrical activity predicted first flatus as much as 5 days (± 22 h) before occurrence. Conclusions In this open, prospective pilot study, noninvasive measurement of colon activity after open abdominal surgery was feasible and predictive of time to first flatus. Interventions such as feeding can potentially be optimized based on this prediction, potentially improving outcomes, decreasing length of stay, and lowering costs.

Keywords Noninvasive wireless patch . Postoperative recovery . Colon myoelectrical activity . First flatus . Ileus . Open abdominal surgery

Introduction complexity of the surgery, degree of bowel handling, and pre- operative comorbidities affecting whether the recovery hap- Gastrointestinal recovery after any visceral surgery is a com- pens over few days, or is a slow prolonged affair lasting plex dynamic process with multiple factors ranging from weeks.1 Delays in the gastrointestinal recovery process or ileus are accompanied by distention of the abdomen, pain, nau- 2,3 Poster presentation The work was presented as a poster at the 2018 sea, vomiting, and the inability to tolerate oral feeding. Digestive Disease Week (DDW) held in Washington D.C, June 2018. Interventions to alleviate the ileus/distention include insertion or reinsertion of a nasogastric tube, instating nil per os and, if 4 * Anand Navalgund necessitated, parenteral nutrition. All of these factors contrib- [email protected] ute not only to patient discomfort, but extend length of stay (LOS), increase hospital resource utilization, and thereby add 5–7 1 G-Tech Medical, Fogarty Institute for Innovation, 2490 Hospital to overall costs. Drive, Suite 310, Mountain View, CA 94040, USA Clinically, the markers of gastrointestinal recovery are noted 2 El Camino Hospital, 2500 Grant Road, Mountain View, CA 94040, by passage of flatus, defecation, and the ability to tolerate solid USA food without significant nausea and vomiting.8 Passage of stool 3 Palo Alto Medical Foundation, Sutter Health, 701 E El Camino Real, or flatus—considered a surrogate for intestinal and anastomotic Mountain View, CA 9404, USA continuity—is often used as the trigger to start stepwise dietary 4 Department of Medicine, Division of Gastroenterology, Stanford orders with the patient’s ability to tolerate each step marking University School of Medicine, 300 Pasteur Drive, their readiness for the subsequent meal. Fast-track programs Stanford, CA 94305, USA J Gastrointest Surg (2019) 23:982–989 983 that promote early feeding in advance of these clinical markers Mountain View, CA. Patients were asked to self-report pas- have shown some success in reducing the incidence of ileus, sage of flatus, bowel movement, and intake of diet through a but not entirely. In a recent study of 513 consecutive colorectal smartphone app. In cases where the patients were not patients who were on an enhanced recovery after surgery smartphone savvy, information was logged for them through (ERAS) protocol, 128 patients (24.7%) needed postoperative daily rounds by the study coordinator. reinsertion of nasogastric tube at the 3.9 ± 2.9 postoperative day.9 This suggests that, while early postoperative feeding is Wireless Patch beneficial to patients in whom recovery is on track, it does not work in cases where they are not ready for it. Immediately following surgery, three disposable wearable At present, there is no reliable measurement that can pre- wireless patches (G-Tech Medical, Fogarty Institute for dict gastrointestinal recovery/diet readiness for patients in ad- Innovation, Mountain View, CA) that acquire myoelectrical vance of these clinical markers that may allow for interven- signals from the gastrointestinal tract were placed on the an- tions or fast-track programs to facilitate timely recovery. terior abdomen. Prior to patch application, the skin was pre- Auscultation for return of bowel sounds, long part of the stan- pared using isopropyl alcohol and NuPrep gel (Weaver and dard of care, is controversial in its usefulness to indicate re- Company, Aurora, CO, USA) to optimize the conductivity covery. Bowel sounds have shown to have poor correlation from skin to electrode and minimize variability between pa- with flatus/defecation and have proved unsuccessful in guid- tients. The variation in body size and tissue thickness between ing diet interventions.10,11 Some authors have recently argued patients was addressed by a compensation factor which uses for discontinuation of the practice.12 their body mass index and a patent-pending compensation Smooth muscle electrical activity on the other hand is di- algorithm that uses certain aspects of the acquired data itself rectly related to gastrointestinal function and motility. to arrive at the correction. Researchers have previously shown a 1:1 correlation between The G-Tech 6-day wearable patch (Fig. 1a) consists of a electrical and mechanical (contractile) events in the colon with flexible substrate material approximately 2.7″ diameter which internally placed electrode-strain gauge force transducers.13–15 is made up of Ag/AgCl electrodes, a medical grade adhesive, Electrical activity in the colon has been reported across a wide and electronics, to acquire, digitize, and transmit myoelectri- range of frequencies, ranging from 0 to 40 cycles per min cal data via Bluetooth Low Energy (BLE) to a paired iPod (cpm).16,17 Researchers have documented the progressive re- Touch App. The patch includes a 3-V CR2354 battery to turn of colonic electrical activity within these frequencies relat- power its electronics. These patches have a runtime of 6 days ed to resolution of postoperative ileus and clinical recovery and were replaced as needed until the patients’ discharge. The following surgery.16–18 These measurements have been per- custom app has a patient interface to enter clinical informa- formed using electrodes placed internally during surgery, a mation, such as overall mobility, diet status, pain control, nausea jor impediment towards broader use of such technology. or emesis, and the return of bowel function. The application To overcome this limitation, we have developed a nonin- periodically uploads the raw data to a cloud server to be vasive wireless patch system that measures electrical activity downloaded and analyzed (Fig. 1b). The G-Tech system is from the gastrointestinal smooth muscles on the abdominal currently investigational. surface. We have previously reported on the co-occurrence of colon frequency peaks in the 12–28 cpm range in the elec- Processing of Myoelectrical Activity Data and Cohort trical activity with that of pressure recordings measured inter- Analysis nally in the colon via the SmartPill across a multitude of subjects.19 Herein, we examine the feasibility and usefulness Figure 2a shows an example of the raw data containing a burst of this measurement from the noninvasive wireless patch sys- of rhythmic colonic myoelectrical activity with the corre- tem in determining gastrointestinal recovery following open sponding frequency spectrum in Fig. 2b showing the peak abdominal surgery. for the rhythmic activity at ~ 20 cpm. Data processing was performed in a custom LabVIEW version 14.0.1 program and included removal of large amplitude artifacts and band- Methods pass filtering, followed by Fourier transformation to frequency space over 10-min time intervals. Peaks in the frequency Patients and Clinical Parameters spectrum were identified in the 12–28 cpm range within each 10-min interval and the area under the curve (AUC) was cal- Nineteen patients who underwent open abdominal surgeries at culated. Cumulative colonic myoelectrical activity was then a community hospital were consented and enrolled in this trial calculated by summing over each 10-min interval the respec- between March 2016 and May 2017. The study was approved tive AUC multiplied by its duration. One unit of colonic myo- by the Institutional Review Board of El Camino Hospital, electrical activity represented in this paper in ADC (analog to 984 J Gastrointest Surg (2019) 23:982–989

GutCheck Motility Monitor

″

Fig. 1 The G-Tech system consists of a wireless patches with onboard on an iPod with a user interface to enter clinical events and acquire data electronics that acquire electrical activity from gastrointestinal smooth from the patches. The app periodically uploads the data to a cloud server muscles and transmit it via Bluetooth LE; and b a custom G-Tech app for data processing and analysis

digital conversion) counts is equivalent to 3.6e−7mV2. were passing flatus and tolerating regular diet without nausea Cohort analysis was performed in a custom program devel- and vomiting and were discharged. oped in Python version 3.5.2 and R version 3.3.1.

Postoperative Orders and Clinical Measurements

Results All 18 patients had postoperative dietary orders of nil per os (NPO) until return of bowel function. Six of the 18 Study Cohort and Clinical Outcomes cases were nutritionally supported with total parentral nutrition (TPN) in addition to jejunal feeding in one case Eighteen patients were considered for the final analysis; one following a Whipple procedure. A nasogastric tube was patient withdrew from the study. Patches were well tolerated used in 15 of the 18 cases through postoperative day 2 at by all patients, with no adverse events noted. The clinical the minimum. Clear liquids were started after affirmation characteristics of the cohort are shown in Table 1. Flatus oc- of passage of flatus or bowel movement, followed by full curred in all cases with an average time to first flatus of liquids and regular diet. Figure 3a shows the close rela- 4.34 days (± 1.5 days). Bowel movement was closely linked tion of time to bowel movements vs time to regular diet. with the first flatus occurring—together or within hours of Similarly, regular diet was tied closely to the length of it—in 9/18 (50%) of the cases. The average time to first bowel stay as shown in Fig. 3b. Operating time and blood loss movement was 5.57 days (± 2.9 days). In two cases, a bowel during the surgery did not have an impact on time to movement never occurred during their stay but the patients flatus or length of stay.

Fig. 2 a Raw data showing burst of rhythmic ~ 20 cpm colonic myoelectrical activity. b Frequency spectrum computed over the raw data demonstrating the ~ 20 cpm peak J Gastrointest Surg (2019) 23:982–989 985

Table 1 Patient characteristics

Subject Procedure Diagnosis Days to Days to Days to Days to (age, sex) first flatus first bowel regular discharge movement diet

64 M Distal pancreatectomy Cystic neoplasm of the pancreatic body 4.5 5.5 5.7 6 70 M Distal pancreatectomy and Pancreatic cancer—tail of pancreas, 4.4 4.4 6.1 7 splenectomy renal metastases 33 M Distal pancreatectomy, splenectomy Pancreatic cancer—mid body of 5.5 9.2 12.3 13 and mobilization of splenic flexure pancreas 73 F Whipple procedure Pancreatic cancer—head of pancreas 3.8 12.4 15.4 16 adenocarcinoma 69 M Whipple procedure (pylorus Cancer of the ampulla of Vater 4.5 – 9.3 10 preserving) 74 M Whipple procedure and feeding Pancreatic cancer—head of pancreas 4.7 5.9 – 32 jejunostomy tube adenocarcinoma and cholestasis secondary to obstructive jaundice 83 F Greater than 3-segment partial Hepatocellular carcinoma 4.3 4.3 5.4 7 hepatectomy, left lobe of the liver, hepatocellular carcinoma 60 F Exploratory laparotomy with lysis of Incisional hernia, acquired deformity 2.7 – 3.1 5 adhesions, reconstruction of anterior of anterior abdominal wall abdominal wall, ventral hernia repair of Strattice biologic mesh, component separation repair and excision of hypertrophic scar 70 F Reversal of colostomy, partial Obstructive perforated colon cancer, 8.7 9.9 10 10 colectomy, lysis of adhesions, and partial colectomy, end colostomy takedown of splenic flexure 82 F Hartman’s end colostomy procedure Perforated sigmoid colon diverticulitis, 4.8 6.1 6.1 6.2 reversal, partial colectomy with Hartmann’sprocedure colorectal anastomosis (handsewn 2 layers) 48 M Low anterior resection, Hartman’send Perforated sigmoid colon diverticulitis, 3.5 3.6 4.8 5 colostomy procedure reversal with Hartmann’sprocedure EEA (end to end) colorectal anastomosis and lysis of adhesions 72 M Low anterior resection with EEA Rectal cancer 2.8 2.9 4.5 6 anastomosis (32-French EEA) 91 M Right colectomy Colon cancer 4.5 4.5 6.4 23 33 M Ileocecectomy, and debridement and Crohn’s disease 3.2 3.2 4.9 6 drainage of abdominal wall abscess 52 F Right hemicolectomy Cecal cancer 4.2 4.2 8.7 9 84 M Sigmoid colectomy Sigmoid volvulus 2.2 2.2 5.1 7 61 M Sigmoid colectomy Recurrent sigmoid colon diverticulitis 3.5 3.5 4.9 5 68 M Left colectomy with primary Colon cancer with liver metastasis 6.3 7.2 10.9 11 anastomosis and mobilization of splenic flexure, resection of the left lateral segment of liver tumor and resection of dome of liver tumor

Myoelectrical Measurements peaks early in the recovery process, compared to the patient with later flatus. Peaks in the 12 to 28 cpm range were consistently observed in all 18 patients compared to the other frequency regions of Time to First Flatus vs Cumulative Colon Activity colon activity and were chosen for analysis. Colonic frequency activity plots, for a patient with later than average flatus and Cumulative colonic activity over the initial 36-h period fol- for a patient with earlier than average flatus, are shown in lowing surgery had a high correlation with time to flatus. The Fig. 4, with the earlier flatus patient demonstrating strong 36-h time period was found to be optimal for such correlation 986 J Gastrointest Surg (2019) 23:982–989

Fig. 3 a Scatter plot of time to regular diet and time to first bowel movement shows a linear relationship. b Scatter plot of time to regular diet and length of stay was also closely linked as shown in Fig. 5. A linear least square fit between time to Time to First Bowel Movement vs Cumulative Colon first flatus and cumulative colonic myoelectrical activity at Activity 36 h (CA36) was calculated. Patients’ predicted time to first flatus is equal to − 1.32E−12 × CA36 + 7.35. The standard de- Similar to time to flatus, an inverse linear relationship was viation in the prediction errors as calculated by the root mean observed between cumulative colonic myoelectrical activity square error (RMSE) for the residuals was 21.7 h. at 36 h and time to first bowel movement as shown in

100 First flatus

Relative amplitude

100 First flatus

Relative amplitude

Discharge

Fig. 4 Colon frequency peak plots for the first 6 days of a representative 2 days post-surgery, compared to the patient with the later first flatus for patient with later than average first flatus and a representative patient with whom onset of activity occurs largely beyond postoperative day 2. The earlier than average first flatus. The patient with the earlier first flatus color gradient represents amplitude of the observed peaks, with the darker demonstrates strong peaks early in the recovery process, within the first color reflecting a stronger peak and the lighter color a weaker peak J Gastrointest Surg (2019) 23:982–989 987

Fig. 5 a Scatter plot of time to first flatus vs cumulative colon myoelectrical activity at 36 h shows an inverse linear relationship; a least squares fit was calculated and the residuals for the fit between the predicted and actual values are shown in b

Fig. 6. A linear least squares fit was calculated. Patients’ time Discussion to first bowel movement is equal to − 1.98E−12 × CA36 + 9.53. The standard deviation in the prediction errors with the This pilot prospective, open clinical trial suggests that colonic RMSE of the residuals was 29.8 h. For the fit, one individual myoelectrical activity, measured on the abdominal surface who had their first flatus on postoperative day 3.8 but did not with a noninvasive wireless patch system, carries predictive have their first bowel movement until day 12.4 (shown as a value in determining time to flatus and time to bowel move- hollow circle) was not included. Their predicted time to first ment following open abdominal surgery. Having such infor- bowel movement would have been 5.7 days. The patient dur- mation in advance of clinical measures could facilitate timely ing this period developed an intra-abdominal infection which interventions, be it early feeding or delaying feeding as dictat- may explain their slow progress. ed by the patient’s unique recovery profile.

Fig. 6 a Scatter plot of time to first bowel movement vs cumulative colon predicted and actual values are shown in b. For the fit, one individual myoelectrical activity at 36 h shows an inverse linear relationship; a least who had their first bowel movement on postoperative day 12.4 was not squares fit was calculated and the residuals for the fit between the included 988 J Gastrointest Surg (2019) 23:982–989

ERAS protocols which promote early feeding, along with opi- frequently. The 12–28 peaks also tend to follow the pattern of oid sparing techniques and use of minimally invasive procedures, intermittent behavior, typical of the colon. Performing colon have been shown to be safe and beneficial for many patients by muscle strip recordings, Huzinga et al. noted that, at frequencies demonstrating earlier recovery and shorter length of stay.9,20,21 above 12 cpm, contractions were likely to be prolonged and of However, it has also been shown that, for as many as 25% of higher amplitude, with increased superimposed spiking cases, the strategy does not work as noted earlier, with the need of activity.31 The 12–28 cpm range is also distinctive from that of reinsertion of the nasogastric tube and reinstating nil per os status. the small intestine which is known to have frequencies in the These findings are similar to our own findings where a third of the mid-range (6–12 cpm), although some researchers have argued patients under the ERAS protocol following a Whipple procedure for the range to be 8–12 cpm with the 8 cpm representing the did not tolerate the early feeding (Am J Physiol. In press). The lower limit for the ileum.11,32,33 Using serosal electrodes, Chen patch system would provide a unique insight into the process et al. observed frequencies centered around 12 cpm for the duo- allowing for a tailored protocol that could improve patient satis- denum and between 9 and 11 cpm for the jejunum.34 At the low faction and optimize recovery. The system could also enable range of frequencies, most often the well-characterized ~ 3 cpm feedback on the impact to the colonic myoelectrical activity of signal from the stomach is observed.35 In a recent study where medications, particularly opioids, used for pain management that we monitored gastric activity using the patch system following are known to inhibit gastrointestinal function by disrupting the pancreaticoduodenectomy (Am J Physiol. In press), cumulative normal recovery patterns of colonic motility.22–24 gastric activity—calculated from peaks in the ~ 3 cpm range— While it remains to be seen, in addition to predicting time to could distinguish patients with shorter and longer times to oral flatus/bowel movement early on, the ability to continue mon- diet. On the whole, it is possible that some peaks in the frequency itoring the patient may allow one to predict onset of secondary ranges below 12 cpm belong to the colon and were subsequently complications, such as wound infections or anastomotic leaks, missed with the current assignment; however, as we have shown that are associated with ileus. Similarly, given the wireless here, the activity in the 12–28 cpm range was sufficiently predic- noninvasive nature of the system, the patients could be tive of recovery and time to flatus following surgery. discharged home with the patches, whereby they would serve Our study has several strengths and limitations. Prospective as a remote monitoring tool. This could be particularly useful in nature, it was performed in an everyday community practice in cases where the patients may have been discharged early setting in a moderate number of patients undergoing open ab- and may be at a high risk for readmission. The system would dominal surgery, and in this respect, its findings could be reflec- then send updates/alerts to the care team for management and tive of general surgical practice. The safety and easy applicabil- potentially avoid preventable readmissions. ity of the patch system were attractive to patients and clinicians Colon myoelectrical activity, as compared to the stomach and alike, while its analyses were robust and reproducible. Obvious the small intestine, is complex, occurring over a wide range of limitations include the lack of prospective evidence on feeding frequencies while an individual segment can oscillate at multiple and other clinical decision-making based on the patch data as frequencies.25–28 In terms of range of frequencies, Sarna et al., well as the validation that this approach can reduce perioperative having placed internal electrodes in 15 patients undergoing cho- length of stay and hospital costs. Nevertheless, our preliminary lecystectomy, have observed frequencies in the 2–40 cpm range, data is quite promising and could be used to guide clinical grouping them in low (2–9cpm),mid(9–13 cpm), and high decision-making in a larger, prospective multicenter clinical trial, where the use and degree of postoperative analgesia and rate (25–40 cpm) ranges.16 In contrast, Stoddard et al. with serosal and range of complications and other parameters contributing to electrodes in the ascending and transverse colon of 20 patients ileus could be better assessed and correlated. only observed frequencies in the 2–4 cpm and 6–12 cpm In conclusion, in an open, prospective pilot study, noninva- ranges.29 One of the major limitations of both of these studies sive measurement of colonic myoelectrical activity after ab- and others during that time was that these recordings were done dominal surgery can predict time to first flatus and first bowel 1 to 2 h per day, thus missing activities that may occur through movement. We believe that this technology objectively iden- the day intermittently. A good example of such activity is the tifies patients that may be at risk for developing postoperative contractile electrical complex (CEC) seen in the higher frequen- ileus and can guide timing of oral intake by Breadiness,^ there- cy ranges.16 The CEC, also known as the colonic migrating by potentially shortening the LOS and decreasing costs. motor complex (CMMC) in the animal model, is the physiological equivalent of the high amplitude propagating contraction Acknowledgements We would like to thank Ryan Schroeder, Director of (HAPC) seen in manometry studies and is responsible for mass Clinical Research, and his team at the El Camino Hospital, Mountain movement of fecal matter,27 that occur only few times a day.30 View, CA, for their help in recruiting and consenting patients for the Testing over 200 individuals using the patch system over study. multiple days (unpublished data), we have noted that most indi- Grant Support Work supported in part by a grant from the Kenneth viduals exhibit well-defined frequencies in the 12–28 cpm range Rainin Foundation. This work also received support from the Fogarty and that Sarna’s low and mid-range frequencies are observed less Institute for Innovation and Breakout Labs. J Gastrointest Surg (2019) 23:982–989 989

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